IPR2015-01103

Paper No. ______ Filed: April 23, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE ____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD ___________________

COALITION FOR AFFORDABLE DRUGS VI LLC

PETITIONER

V.

CELGENE CORPORATION

PATENT OWNER

___________________

CASE NO.: UNASSIGNED PATENT NO. 6,315,720

FILED: OCTOBER 23, 2000 ISSUED: NOVEMBER 13, 2001

INVENTORS: BRUCE A. WILLIAMS, JOSEPH K. KAMINSKI

TITLE: METHODS FOR DELIVERING A DRUG TO A PATIENT WHILE AVOIDING THE OCCURRENCE OF AN ADVERSE SIDE EFFECT KNOWN

OR SUSPECTED OF BEING CAUSED BY THE DRUG ___________________

PETITION FOR INTER PARTES REVIEW

OF U.S. PATENT NO. 6,315,720

Patent No. 6,315,720

TABLE OF CONTENTS

I. INTRODUCTION................................................................................................... 1

II. GROUNDS FOR STANDING (37 C.F.R. 42.104(a)) ..................................... 1

III. MANDATORY NOTICES (37 C.F.R. 42.8) ..................................................... 1

A. Real Parties-in-Interest (37 C.F.R. 42.8(b)(1)) .................................................... 1

B. Related Judicial and Administrative Matters (37 C.F.R. 42.8(b)(2)) ................. 2

C. Lead and Back-Up Counsel (37 C.F.R. 42.8(b)(3)) and Service Information (37 C.F.R. 42.8(b)(4)) ....................................................................... 3

IV. PAYMENT OF FEES (37 C.F.R. 42.15(a) and 42.103) ................................ 3

V. IDENTIFICATION OF CHALLENGE ............................................................. 3

A. Overview of U.S. Patent No. 6,315,720 ................................................................. 3

1. The 720 Patent Specification ............................................................................. 4

2. The 720 Claims .................................................................................................... 5

3. The 720 Prosecution History ............................................................................. 6

B. Claim Construction of Challenged Claims ............................................................. 9

1. Consulted ......................................................................................................... 10

2. Teratogenic effect ........................................................................................... 10

3. Adverse side effect ......................................................................................... 11

C. Statement of Precise Relief Requested for Each Claim Challenged ................. 11

1. Claims for Which Review is Requested ........................................................... 11

2. Statutory Grounds of Challenge ....................................................................... 11

D. Overview of the State of the Art and Motivation to Combine ......................... 11

1. Summary of the Petitions Prior Art References ............................................ 14

E. Level of Ordinary Skill in the Art .......................................................................... 17

VI. DETAILED EXPLANATION OF THE CHALLENGE .............................. 17

A. Ground 1: Claims 132 of U.S. Patent No. 6,315,720 are obvious under 35 U.S.C. 103(a) over Mitchell in view of

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Dishman and in further view of Cunningham and the knowledge of one of ordinary skill in the art. .......................................................................... 17

1. Claim 1 is obvious over Mitchell in view of Dishman and in further view of Cunningham. .............................................................................. 17

2. Dependent Claims 26 are obvious over the prior art of Ground 1, and more specifically over Mitchell in view of Dishman and in further view of the knowledge of one of ordinary skill in the art. ..................................................................................... 25


4. Dependent Claims 1114 and 2025 are obvious over the prior art of Ground 1, and more specifically over Mitchell in view of the knowledge of one of ordinary skill in the art. ............................ 31

5. Dependent Claim 15 is obvious over the prior art of Ground 1, and more specifically over Mitchell in view of Dishman and in further view of the knowledge of one of ordinary skill in the art. ............... 35


7. Dependent Claims 1819 and 2627 are obvious over the prior art of Ground 1, and more specifically over Mitchell in view of Dishman and in further view of the knowledge of one of ordinary skill in the art. ................................................................................. 38

8. The added limitations of independent Claim 28 and dependent Claims 2932 are obvious over Mitchell in view of Dishman and in further view of Cunningham and knowledge of one of ordinary skill in the art. ..................................................................................................... 41

9. Claim chart for Ground 1 showing exemplary citations in Mitchell, Dishman, and Cunningham. ................................................................... 46

VII. CONCLUSION ...................................................................................................... 60

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TABLE OF AUTHORITIES

Cases Abbott Labs v. Andrx Pharms., Inc.,

452 F.3d 1331 (Fed. Cir. 2006) ....................................................................................... 24 Bayer Schering Pharma AG v. Barr Labs., Inc.,

575 F.3d 1341 (Fed. Cir. 2009) ....................................................................................... 23 Dow Chem. Co. v. Sumitomo Chem. Co.,

257 F.3d 1364 (Fed. Cir. 2001) ....................................................................................... 18 Dystar Textilfarben GmbH v. C.H. Patrick Co.,

464 F.3d 1356 (Fed. Cir. 2006) ....................................................................................... 25 In re Glatt Air Techniques, Inc.,

630 F.3d 1026 (Fed. Cir. 2011) ....................................................................................... 18 In re Icon Health & Fitness, Inc.,

496 F.3d 1374 (Fed. Cir. 2007) ....................................................................................... 19 In re Kahn,

441 F.3d 977 (Fed. Cir. 2006) ......................................................................................... 43 In re Venner,

262 F.2d 91 (C.C.P.A. 1958) ........................................................................................... 38 KSR Intl Co. v. Teleflex Inc.,

550 U.S. 398 (2007) ....................................................................................... 23, 24, 40, 41 Pacing Techs., LLC v. Garmin Intl, Inc.,

778 F.3d 1021 (Fed. Cir. 2015) ....................................................................................... 10 Par Pharm., Inc. v. TWi Pharms., Inc.,

773 F.3d 1186 (Fed. Cir. 2014) ........................................................................... 20, 22, 44 Pentec, Inc. v. Graphic Controls Corp.,

776 F.2d 309 (Fed. Cir. 1985) ...................................................................... 18, 28, 33, 42 Pfizer, Inc. v. Apotex, Inc.,

480 F.3d 1348 (Fed. Cir. 2007) ....................................................................................... 21 Rogers v. Desa Intl, Inc.,

198 Fed. Appx. 918 (Fed. Cir. 2006) ............................................................................. 21 Sciele Pharma, Inc. v. Lupin Ltd.,

684 F.3d 1253 (Fed. Cir. 2012) ................................................................................. 34, 45 Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc.,

774 F.3d 968 (Fed. Cir. 2014) ................................................................................... 21, 30

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Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352 (Fed. Cir. 2011) ....................................................................................... 31

Rules 37 C.F.R. 42.103 .................................................................................................................. 3 37 C.F.R. 42.15(a) ................................................................................................................ 3 37 C.F.R. 42.8(b)(1) ............................................................................................................. 1

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TABLE OF EXHIBITS

Exhibit No. Description Exhibit 1001 U.S. Patent No. 6,315,720 to Bruce A. Williams and Joseph K.

Kaminski, filed on Oct. 23, 2003, and issued on Nov. 13, 2001 (the 720 Patent)

Exhibit 1002 U.S. Patent No. 6,315,720 Prosecution History (720 prosecution history)

Exhibit 1003 U.S. Patent No. 6,045,501 to Marc Elsayed and Bruce Williams, filed on Aug. 28, 1998, and issued on Apr. 4, 2000 (Elsayed)

Exhibit 1004 U.S. Patent No. 6,063,026 to Mark A. Schauss and Patricia Kane, filed on Mar. 22, 1996, and issued on May 16, 2000 (Schauss)

Exhibit 1005 U.S. Patent No. 6,202,923 to Joseph H. Boyer et al., filed on Aug. 23, 1999, and issued on Mar. 20, 2001 (Boyer)

Exhibit 1006 Guideline for the clinical use and dispensing of thalidomide, R.J. Powell and J.M.M Gardner-Medwin, Postgrad Med. J. (1994) 79, 901904 (Powell)

Exhibit 1007 Pharmacists role in clozapine therapy at a Veterans Affairs medical center, Benjamin R. Dishman et al., Am. J. Hosp. Pharm. (Apr. 1, 1994) 51, 899901 (Dishman)

Exhibit 1008 U.S. Patent No. 5,832,449 to David W. Cunningham, filed on Nov. 13, 1995, and issued on Nov. 3, 1998 (Cunningham)

Exhibit 1009 U.S. Patent No. 6,055,507 to David W. Cunningham, filed on Aug. 20, 1998, and issued on Apr. 25, 2000 (Cunningham Divisonal)

Exhibit 1010 A Pregnancy-Prevention Program in Women of Childbearing Age Receiving Isotretinoin, Allen A. Mitchell et al., New Eng. J. Med. (Jul. 13, 1995) 333:2, 10106 (Mitchell)

Exhibit 1011 S.T.E.P.S.TM: A Comprehensive Program for Controlling and Monitoring Access to Thalidomide, Jerome B. Zeldis et al., Clinical Therapeutics (1999) 21:2, 31930 (Zeldis)

Exhibit 1012 Transcript of the FDAs Forty-Seventh Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee, Sept. 4, 1997 (FDA Meeting Part 1)

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Exhibit No. Description Exhibit 1013 Transcript of the FDAs Forty-Seventh Meeting of the

Dermatologic and Ophthalmic Drugs Advisory Committee, Sept. 5, 1997 (FDA Meeting Part 2)

Exhibit 1014 CDC Meeting: 03/26/1997 Minutes and Agenda Regarding Thalidomide (CDC Meeting)

Exhibit 1015 Assessing the Effectiveness of a Computerized Pharmacy System, Reed M. Gardner et al., Decision Support Systems in Critical Care, 1994, M.M. Schabot et al., eds. (Gardner)

Exhibit 1016 Review of computer applications in institutional pharmacy19751981, Ken W. Burleson, Am. J. Hosp. Pharm. (1982) 39:5370 (Burleson)

Exhibit 1017 Interactive Voice Response Systems in Clinical Research and Treatment, James C. Mundt, Psychiatric Services (May 1997) 48:5, 61112, 623 (Mundt)

Exhibit 1018 Passage of Chemicals into Human and Animal Semen: Mechanisms and Significance, Thaddeus Mann and Cecelia Lutwak-Mann, CRC Critical Reviews in Toxicology (1982) 11:1, 114 (Mann)

Exhibit 1019 Preparing for Thalidomides Comeback, Cori Vanchieri, Annals of Internal Med. (Nov. 15 1997) 127:10, 95154 (Vanchieri)

Exhibit 1020 Development of a Computerized Drug Interaction Database (MedicomSM) for Use in a Patient Specific Environment, Arthur F. Shinn et al., Drug Inform. J. (1983) 17:20510 (Shinn)

Exhibit 1021 Decision support for drug prescription integrated with computer-based patient records in primary care, R. Linnarsson, Med. Inform. 18:2, 13142 (Linnarsson)

Exhibit 1022 A medication database a tool for detecting drug interactions in hospital, P.E. Grnroos et al., Eur. J. Clin. Pharmacol. (1997) 53:1317 (Grnroos)

Exhibit 1023 Prevalence of Alcohol and Drug Abuse in Schizophrenic Inpatients, M. Soyka et al., Eur. Arch. Psychiatry Clin. Nerosci. (1993) 242:36272 (Soyka)

Exhibit 1024 Alcohol, Cannabis, Nicotine, and Caffeine Use and Symptom Distress in Schizophrenia, Edna Hamera et al., J. of Nervous and Mental Disease (Sept. 1995) 183:9, 55965 (Hamera)

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Exhibit No. Description Exhibit 1025 Substance Abuse and Schizophrenia: Editors Introduction,

Thomas R. Kosten and Douglas M. Ziedonis, Schizophrenia Bulletin (1997) 23:2, 18186 (Kosten)

Exhibit 1026 Substance Abuse and Women on Welfare, Jeffrey C. Menill, National Center on Addiction and Substance Abuse at Columbia University, June 1994 (Menill)

Exhibit 1027 Declaration of Jeffrey Fudin, R.Ph., B.S., Pharm.D., DAAPM, FCCP, FASHP (Fudin Decl.)

Exhibit 1028 Curriculum Vitae for Jeffrey Fudin, R.Ph., B.S., Pharm.D., DAAPM, FCCP, FASHP (Fudin CV)

Exhibit 1029 Center for Drug Evaluation and Research Approval Package for Application Number: 18-662/S-038 (Accutane Label)

Exhibit 1030 Joint Claim Construction and Prehearing Statement, Celgene Corp. v. Natco Pharma Ltd., NJD-2-10-cv-05197, Jul. 18, 2011 (Celgene Claim Construction Brief)

Exhibit 1031 Center for Drug Evaluation and Research Approval Package for: Application Number NDA 20-785 Approval Letter(s), Sept. 19, 1997, and Jul. 16, 1998 (FDA Thalomid Approval Letters)

Exhibit 1032 Influence of Socially Desirable Responding in a Study of Stress and Substance Abuse, John W. Welte and Marcia Russell, Alcohol. Clin. Exp. Res. (Jul./Aug. 1993) 17:4, 75861 (Welte)

Exhibit 1033 Thalidomide BackUnder Strict Control, JAMA: Medical News and Perspectives (Oct. 8, 1997) 278:14, 113537 (JAMA)

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I. INTRODUCTION

Petitioner Coalition For Affordable Drugs VI LLC (CFAD), requests an Inter

Partes Review (IPR) of Claims 132 (collectively, the Challenged Claims) of U.S.

Patent No. 6,315,720 (the 720 Patent) (Ex. 1001) in accordance with 35 U.S.C.

31119 and 37 C.F.R. 42.100 et seq.

II. GROUNDS FOR STANDING (37 C.F.R. 42.104(A))

Pursuant to 37 C.F.R. 42.104(a), Petitioner certifies that the 720 Patent is

available for IPR and that Petitioner is not barred or estopped from requesting IPR

challenging the Claims of the 720 Patent on the grounds identified in this Petition.

III. MANDATORY NOTICES (37 C.F.R. 42.8)

A. Real Parties-in-Interest (37 C.F.R. 42.8(b)(1))

Pursuant to 37 C.F.R. 42.8(b)(1), Petitioner certifies that Coalition For

Affordable Drugs VI LLC (CFAD VI), Hayman Credes Master Fund, L.P.

(Credes), Hayman Orange Fund SPC Portfolio A (HOF), Hayman Capital

Master Fund, L.P. (HCMF), Hayman Capital Management, L.P. (HCM), Hayman

Offshore Management, Inc. (HOM), Hayman Investments, L.L.C. (HI), nXn

Partners, LLC (nXnP), IP Navigation Group, LLC (IPNav), J. Kyle Bass, and

Erich Spangenberg are the real parties in interest (collectively, RPI). The RPI

hereby certify the following information: CFAD VI is a wholly owned subsidiary of

Credes. Credes is a limited partnership. HOF is a segregated portfolio company.

HCMF is a limited partnership. HCM is the general partner and investment manager

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of Credes and HCMF. HCM is the investment manager of HOF. HOM is the

administrative general partner of Credes and HCMF. HI is the general partner of

HCM. J. Kyle Bass is the sole member of HI and sole shareholder of HOM. CFAD

VI, Credes, HOF and HCMF act, directly or indirectly, through HCM as the general

partner and/or investment manager of Credes, HOF and HCMF. nXnP is a paid

consultant to HCM. Erich Spangenberg is the 98.5% member of nXnP. IPNav is a

paid consultant to nXnP. Erich Spangenberg is the 98.5% member of IPNav. Other

than HCM and J. Kyle Bass in his capacity as the Chief Investment Officer of HCM

and nXnP and Erich Spangenberg in his capacity as the Manager/CEO of nXnP, no

other person (including any investor, limited partner, or member or any other person

in any of CFAD VI, Credes, HOF, HCMF, HCM, HOM, HI, nXnP or IPNav) has

authority to direct or control (i) the timing of, filing of, content of, or any decisions or

other activities relating to this Petition or (ii) any timing, future filings, content of, or

any decisions or other activities relating to the future proceedings related to this

Petition. All of the costs associated with this Petition will be borne by HCM, CFAD

VI, Credes, HOF and/or HCMF.

B. Related Judicial and Administrative Matters (37 C.F.R. 42.8(b)(2))

Pursuant to 37 C.F.R. 42.8(b)(2), Petitioner states that the 720 Patent has

been the subject of the following lawsuits: Celgene Corp. et al. v. Lannett Holdings, Inc. et

al., NJD-2-15-00697 (filed Jan. 30, 2015); Celgene Corp. v. Natco Pharma Ltd., NJD-2-10-

cv-05197 (filed Oct. 8, 2010); Celgene Corp. et al. v. Barr Laboratories, Inc. et al., NJD-2-

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08-cv-03357 (filed July 3, 2008); Celgene Corp. et al. v. Barr Laboratories, Inc. et al., NJD-2-

07-cv-05485 (filed Nov. 14, 2007); Celgene Corp. et al. v. Barr Laboratories, Inc. et al., NJD-

2-07-cv-04050 (filed Aug. 23, 2007); Celgene Corp. et al. v. Barr Laboratories, Inc. et al.,

NJD-2-07-cv-00286 (filed Jan. 18, 2007).

C. Lead and Back-Up Counsel (37 C.F.R. 42.8(b)(3)) and Service Information (37 C.F.R. 42.8(b)(4))

Lead counsel is Sarah E. Spires, Reg. No. 61,501,

[email protected]. Back-up counsel are Ki O, Reg. No. 68,952,

[email protected]; Dr. Parvathi Kota, Reg. No. 65,122,

[email protected]; and Paul J. Skiermont (pro hac vice requested),

[email protected] of Skiermont Puckett LLP, 2200 Ross

Ave. Ste. 4800W, Dallas, Texas 75201, P: 214-978-6600/F: 214-978-6601. Petitioner

consents to electronic service.

IV. PAYMENT OF FEES (37 C.F.R. 42.15(a) and 42.103)

The required fees are submitted herewith in accordance with 37 C.F.R.

42.103(a) and 42.15(a). If any additional fees are due during this proceeding, the

Office is authorized to charge such fees to Deposit Account No. 506293. Any

overpayment or refund of fees may also be deposited in this Deposit Account.

V. IDENTIFICATION OF CHALLENGE

A. Overview of U.S. Patent No. 6,315,720

The 720 Patent is titled Methods for Delivering a Drug To A Patient While

Avoiding The Occurrence Of An Adverse Side Effect Known Or Suspected Of Being 3


Caused By The Drug. (Ex. 1001 at Front Cover.) The underlying application, U.S.

Patent Application Serial No. 09/694,217, was filed on October 23, 2000. The 720

Patent issued to Bruce Williams and Joseph K. Kaminski on November 13, 2001. (Id.)

1. The 720 Patent Specification

The 720 Patent claims methods for delivering a drug to a patient, while

avoiding the occurrence of adverse side effects. (Ex. 1001 at Abstract.) The 720

Patent generally describes methods for the distribution to patients of drugs,

particularly teratogenic drugs, in ways wherein such distribution can be carefully

monitored and controlled. (Id. at 1:1316.) A teratogenic drug can cause severe birth

defects when administered to a pregnant woman. (Id. at 1:2729.) The 720

specification acknowledges that prior [m]ethods for monitoring and educating

patients to whom a drug is distributed have been developed in connection with a

known teratogenic drug (isotretinoin), including a pregnancy prevention program.

(Id. at 2:1320.)

The invention of the 720 Patent was allegedly conceived in the context of the

FDA approval of thalidomidea teratogenic drug effective in treating a variety of

diseaseswhen the inventors were seeking methods to control the distribution of

[thalidomide] so as to preclude administration to fetuses. (Id. at 1:4664.)

The 720 Patents invention can be summarized as: (1) filling prescriptions only

after consulting a computer readable storage medium to confirm that the prescribers,

pharmacies, and patients are registered in a computer database; (2) assigning patients

4


to risk groups based on the risk that the drug will cause adverse side effects and

entering the risk group assignment in the storage medium; (3) determining the

acceptability of the likely adverse effect; and (4) generating a prescription approval

code to said pharmacy before said prescription is filled. (Id. at 2:493:4.) The 720

Patent specification also teaches that [t]he invention is not limited to the distribution

of teratogenic drugs; other potentially hazardous drugs may also be distributed in

accordance with embodiments of this invention in such a fashion that persons for

whom such drugs are contraindicated will not receive them. (Id. at 3:2126.)

The patent also discloses that when a patient is registered in the computer

readable storage medium, information probative of the risk of a drugs side effects is

also collected from the patient. (Id. at 6:3033.) This information can then be

compared with a defined set of risk parameters for the drug, allowing for assignment

of the patient to a particular risk group. (Id. at 6:3336.) If the risk of adverse side

effects is deemed acceptable, the patient may receive the drug from a registered

pharmacy, subject to conditions such as a negative pregnancy test, but may not receive

refills without a renewal prescription from the prescriber. (Id. at 11:6212:8.)

2. The 720 Claims

The 720 Patent has two independent claims and 30 dependent claims. Claim 1

is representative and is reproduced below.

In a method for delivering a drug to a patient in need of the drug, while

avoiding the occurrence of an adverse side effect known or suspected of

5


being caused by said drug, wherein said method is of the type in which

prescriptions for said drug are filled only after a computer readable

storage medium has been consulted to assure that the prescriber is

registered in said medium and qualified to prescribe said drug, that the

pharmacy is registered in said medium and qualified to fill the

prescription for said drug, and the patient is registered in said medium

and approved to receive said drug, the improvement comprising:

a. defining a plurality of patient risk groups based upon a

predefined set of risk parameters for said drug;

b. defining a set of information to be obtained from said patient,

which information is probative of the risk that said adverse side effect is

likely to occur if said drug is taken by said patient;

c. in response to said information set, assigning said patient to at

least one of said risk groups and entering said risk group assignment in

said medium;

d. based upon said information and said risk group assignment,

determining whether the risk that said adverse side effect is likely to

occur is acceptable; and

e. upon a determination that said risk is acceptable, generating a

prescription approval code to be retrieved by said pharmacy before said

prescription is filled.

(Id. at 18:1742.) All other claim limitations are listed within Ground 1 below.

3. The 720 Prosecution History

During prosecution of U.S. Patent Application No. 09/694,217 (filed October

23, 2000), which led to the 720 Patent, the Examiner initially rejected Claims 127 as

obvious under 35 U.S.C. 103(a) over U.S. Patent No. 6,045,501 (Ex. 1003, Elsayed)

6


in view of U.S. Patent No. 6,063,026 (Ex. 1004, Schauss). (See Ex. 1002 at 5758.1)

At this time, Claims 132 were pending. (Id. at 56.) Claim 1, the only independent

claim, recited a method for delivering a drug to a patient in need of the drug while

avoiding the occurrence of an adverse side effect known or suspected of being caused

by said drug. (Id. at 44.)

The Examiner rejected Claims 127, stating that Elsayed suggested the use of

the information to evaluate risk levels, while Schauss taught a medical diagnostic

analysis system that evaluates patient data obtained from medical testing or patient

questioning for drugs contraindications. (Id. at 58.) The Examiner concluded that it

would have been obvious to one of ordinary skill in the art at the time of the invention

to implement the screening for drug contraindications suggested in Elsayed et al. with

the method of Schauss et al., since Schauss et al. teach the particular steps for

performing the analysis. (Id. at 58.) Regarding Claim 6, the Examiner stated that

although Elsayed does not specifically teach that data received by facsimile

transmission is entered by an OCR software, it is inherent that this data must be

entered into database. (Id. at 58.) The Examiner also objected to Claims 2832 as

being dependent upon a rejected base claim, but would be allowable if rewritten in

independent form. (Id. at 59.)

1 Except for the prosecution history, exhibit cites herein are directed to the internal

page numbers of the exhibit, rather than to the Exhibits Bates numbers.

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In response, applicants amended Claim 1 by adding, among other limitations,

upon a determination that said risk is acceptable, generating a prescription approval

code to be retrieved by said pharmacy before said prescription is filled. (Id. at 87.)

Based on this amendment, applicants argued that Elsayed, although teaching a

method which contains many of the steps of the present invention, contains no

disclosure of the generation of a prescription approval code as recited in amended

Claim 1. (Id. at 85.) Applicants further argued that [a]lthough Schauss may describe

a medical diagnostic analysis system that evaluates patient data obtained from

questioning a patient or medical testing, Schauss contains no disclosure remotely

related to the generation of a prescription approval code, this being the subject of

Applicants claims. (Id. at 86.)

In response, the Examiner rejected the claims as obvious over Elsayed in view of

Schauss and Boyer, U.S. Patent No. 6,202,923 (Ex. 1005, Boyer ), which includes a step

for generating a prescription number or code associated with said prescription by a

computer workstation. ( Id. at 9192.)

In response, applicants argued:

As amended on March 23, 2001, Claim 1 further requires an assessment,

based upon the risk group assignment and the information collected

from the patient, as to whether the risk of the side effect occurring is

acceptable. Upon a determination that the risk is acceptable, and only upon

such a determination, a prescription approval code is generated, which must

be retrieved by the pharmacy before the prescription may be filled. Thus,

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the prescription approval code is not merely a number that is associated

with the prescription, but instead represents the fact that a determination

has been made that the risk of the side effect occurring is acceptable, and

that approvalan affirmative decisionhas been made for the

prescription to be filled. Boyer does not disclose or suggest such an

approval code.

(Id. at 10607.) Applicants further argued that in Boyer, the prescription number is

simply an identifier for the prescription, and is not an approval code, as recited in

Applicants claims, and that Boyer provides no indication that a prescription approval

code, as described and claimed in the instant application, must be generated and

retrieved by the pharmacist before the prescription may be filled. (Id. at 107.)

The applicants amended Claim 28 to be an independent claim, and then argued

that because [a]ny proper combination of the disclosure of Boyer with that of

Elsayed and Schauss does not teach or suggest the invention defined by Applicants

claims, the Examiner should withdraw the 103 rejection. (Id. at 10607.)

After this response, all of the 720 Patent claims were allowed. (Id. at 111.)

B. Claim Construction of Challenged Claims

A claim subject to IPR receives the broadest reasonable construction in light

of the specification of the patent in which it appears. 37 C.F.R. 42.100(b); see In re

Cuozzo Speed Techs., LLC, 778 F.3d 1271, 1279 (Fed. Cir. 2015). In applying such a

standard, the broadest reasonable construction of claim language is not one that

permits any reading, but instead is one that must be made in light of the specification

9


as it would be interpreted by one of ordinary skill in the art. In re Am. Acad. of Sci.

Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004) (citation omitted).

Unless otherwise noted, Petitioner accepts, for purposes of IPR only, that the

claim terms of the 720 Patent are presumed to take on the ordinary and customary

meaning that they would have to one of ordinary skill in the art.2

1. Consulted

Consulted means accessed and considered. (Ex. 1030 at 3; Ex. 1027 39.)

2. Teratogenic effect

Teratogenic effect means any effect that disturbs the normal growth and

development of an embryo or fetus. (Ex. 1030 at 2; Ex. 1027 40.)

2 Petitioner notes that, in some instances, the patentee has defined claim terms apart

from their plain meaning. See Pacing Techs., LLC v. Garmin Intl, Inc., 778 F.3d 1021,

1024 (Fed. Cir. 2015). These terms include drug, computer readable storage

medium, patient risk groups, risk parameters, risk group assignment, likely to

occur, prescription approval code, counseled, risk avoidance measures, and

informed consent. (Ex. 1001 at 3:3538, 3:4548, 4:5456, 5:2933, 6:307:19,

8:4557, 9:826, 10:4146, 13:4464.)

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3. Adverse side effect

Adverse side effect means any unfavorable abnormality, defect, mutation,

lesion, degeneration or injury which may be caused by taking the drug. (Ex. 1030 at

3; Ex. 1027 41; see Ex. 1001 at 3:3844.)

C. Statement of Precise Relief Requested for Each Claim Challenged

1. Claims for Which Review is Requested

Petitioners request IPR under 35 U.S.C. 311 of Claims 132 of the 720

Patent, and cancellation of these 32 claims as unpatentable.

2. Statutory Grounds of Challenge

Petitioners request IPR of Claims 132 of the 720 Patent in view of the

following references, each of which is prior art to the 720 Patent under 35 U.S.C.

102(a) and (b) or 103. The Examiner did not reference any of the prior art listed in

the following chart in any Office Action. (See generally, Ex. 1002.) Claims 132 are

unpatentable under 35 U.S.C. 103:

Ground Proposed Rejections for the 720 Patent Exhibit Number(s) 1 Claims 132 are obvious under 35 U.S.C. 103(a) in

view of Mitchell (Ex. 1010), Dishman (Ex. 1007), and

Cunningham (Ex. 1008).

1007, 1008, and 1010

D. Overview of the State of the Art and Motivation to Combine

By October of 2000, it was well recognized in the art that teratogenic drugs

which can cause birth defectsneeded to be regulated. (See, e.g., Ex. 1006 at 90104;

11


Ex. 1010 at 10105.) The central regulatory goal was to avoid pregnancy in patients

treated with the drug. (See, e.g., Ex. 1010 at 101.) One notable case of a drug marketed

through methods to prevent its use in pregnant patients is isotretinoin, marketed

under the trade name Accutane. (See Ex. 1010 at 101.) Rather than remove this drug

from the market once its teratogenicity was realized, isotretinoin became part of a

manufacturer-sponsored Pregnancy Prevention Program (PPP). (Ex. 1010 at 101.)

The program, among other features, included the distribution to physicians of a kit

that included informed consent documents and patient counseling information.

(Ex. 1010 at 101.) In particular, patients were warned against the teratogenic risk of

isotretinoin and the need to prevent pregnancy. (Ex. 1010 at 105.) Patients were also

advised as to effective available methods of birth control. (See Ex. 1010 at 103.)

Thalidomide is a drug that originated in Germany in 1957. (Ex. 1001 at 1:40

41.) Doctors initially prescribed the drug as a sedative, but quickly noticed its

effectiveness in treating a form of leprosy, erythema nodosum leprosum (ENL), as

well. (Ex. 1011 at 32021.) However, shortly after thalidomide came on the market,

doctors realized that the drug caused severe birth defects in infants whose mothers

took the drug while pregnant. (Ex. 1011 at 320.) As a result, thalidomide was generally

taken off of most markets by 1962. (Ex. 1001 at 1:4445.) Due to thalidomides

therapeutic effects, the drug was reintroduced in the United States in the 1990s with

the understanding it could be marketed only with strict controls, and gained FDA

approval to treat ENL in 1998. (See Ex. 1006 at 901; Ex. 1011 at 320.) 12


Doctors and pharmacists interested in bringing thalidomide to the market with

restrictions to protect from its teratogenic effects considered the Accutane PPP, with

its focus on counseling, as a starting point. (Ex. 1012 at 11011; see Ex. 1014 at 1.)

They also considered modeling a thalidomide program on experiences with other

hazardous drugs, including clozapine (trade name Clozaril). (Ex. 1012 at 11112.)

As early as 1997, medical professionals observed that the prescription control

methods for clozapine, an anti-depressant with potential adverse effects indicated by

white blood cell counts (WBCs), could be copied for thalidomide. (Ex. 1012 at

112.) In particular, these prescription control methods included keeping records of

patients taking the drug, as well as physicians and pharmacists pre-approved to

prescribe and dispense the drug. (Ex. 1007 at 899900; see Ex. 1012 at 11519;

Ex. 1014 at 9, 24.) The clozapine patients were additionally required to submit to

weekly WBC testing and could only have a prescription for clozapine filled if the test

results fell within a pre-designated range. (Ex. 1007 at 899; see Ex. 1012 at 112;

Ex. 1014 at 8.)

It was also well known in the art prior to 2000 that prescription records can

be kept in a computerized system. (See, e.g., Ex. 1015 at 174; Ex. 1016 at 56, 6063,

68; Ex. 1027 56.) Such records would include information about the patient such as

their sex, height, weight, allergies, and other health-related measures. (See Ex. 1016 at

59; Ex. 1027 56.) Physicians and pharmacists had used computerized systems to

track their patients since at least 1975. (See, e.g., Ex. 1016 at 53; Ex. 1015 at 174, 18213


83.) Practitioners then used this data to determine (1) whether to prescribe a drug to a

particular patient, and (2) how long a patient should take the medication. (See Ex. 1016

at 53, 6367.)

Thus, in the case of thalidomide or any teratogenic drug, those of ordinary skill

in the art would have beenand indeed weremotivated to combine the method

for avoiding pregnancy with a computerized tracking system that only permits filling

prescriptions for the drug when certain conditions (e.g., non-pregnancy) are met. (See

Ex. 1033 at 1136 (Celgene has drafted a plan that it hopes will prevent fetal exposure

to the drug. The plan is built on experience with restrictions on such other drugs

with severe adverse effects as Accutane , used to treat severe acne, and Clozaril

, used to treat schizophrenia [and] a tracking system would be in place to ensure

compliance.); Ex.1012 at 11112; Ex. 1027 5960.)

1. Summary of the Petitions Prior Art References

a. Mitchell (Ex. 1010)

Mitchell constitutes prior art under 35 U.S.C. 102(b) because it was published

in 1995. (Ex. 1010 at Cover.) During prosecution of the 720 Patent, the examiner did

not consider this reference. (See Ex. 1001 at Cover.)

Mitchell discloses a pregnancy prevention program implemented to minimize

pregnancies among women treated with the known teratogenic drug isotretinoin. (See

Ex. 1010 at 10105.) The program sought to keep the drug available while

minimizing the teratogenic hazard. (Id. at 105.) Additionally, the programtargeted

14


at both prescribers and patientsinstructed prescribers to warn patients of risks,

obtain negative pregnancy tests, and delay therapy until the second or third day of the

next normal menstrual period. (Id. at 101.) The program also provided materials to

patients such as information brochures and contraceptive information. (Id. at 101.)

Mitchell also describes counseling patients in relation to isotretinoins

teratogenic effects. (Id. at 105.) Some implementations of the program included

warnings about the need to have a negative blood pregnancy test before starting

therapyand to use effective birth control one month before starting therapy, during

therapy, and one month after completing it. (Id. at 103.)

b. Dishman (Ex. 1007)

Dishman constitutes prior art under 35 U.S.C. 102(b) because it was published

in 1989. (Ex. 1007 at 899.) During the prosecution of the 720 Patent, the examiner

did not consider this reference. (See Ex. 1001 at Cover.)

Dishman discloses a program for controlling the dispensing of clozapine, an

antipsychotic drug, to veterans. (Ex. 1007 at 899.) Clozapine is associated with the

life-threatening side effect of agranulocytosis. (Ex. 1012 at 112.) Dishman describes a

monitoring program instituted by the Department of Veterans Affairs (VA) in 1991

to prevent contraindicated individuals from receiving clozapine. (Ex. 1007 at 900.)

Specifically, Dishman teaches that the VAs program established a National

Clozapine Coordinating Center (NCCC) to review each clozapine candidates file

before granting approval for use and weekly tracking. (Id. at 900.) Prior to this

15


approval, each patient underwent extensive evaluation and documentation to identify

contraindications, including pregnancy. (Id. at 900.) Additionally, for prescription or

use of clozapine, prescribers and patients had to register with the Clozaril National

Registry, which requires weekly monitoring of a patients white blood cell counts and

limits the quantity of medicine dispensed at one time. (Id. at 899.) This process

requires the cooperation and coordinated efforts of the patient, physician, laboratory,

and pharmacy. (Id. at 899.) The NCCC also mandated that each hospital have a

computerized clozapine prescription lockout system, which tied the hospitals

laboratory database to the outpatient pharmacy dispensing software. (Id. at 900.) Thus,

clozapine prescriptions could only be processed when certain pre-defined clinical

criteria were metspecifically, when white blood cell counts were within defined

limits. (Id. at 899.)

c. Cunningham (Ex. 1008)

The Cunningham patent constitutes prior art under 35 U.S.C. 102(b) because it

was filed in 1995 and granted in 1998. (Ex. 1008 at Cover.) During the prosecution of

the 720 Patent, the examiner did not consider this reference. (See Ex. 1001 at Cover.)

The examiner did consider, but did not cite, a divisional of this reference. (See

Ex. 1001 at Cover; Ex. 1010 at Cover.)

Cunningham discloses a method of dispensing pharmaceutical product samples

by linking prescribers and pharmacies to a central computing station. (Ex. 1008 at

Cover.) Specifically, before filling any prescription for a pharmaceutical trial product,

16


the pharmacy must upload defined information into the central computing station.

(See id. at 11:613.) Only if the central computing station establishes that the uploaded

information is valid can the central computing station issue a pharmacy approval code

for the pharmacy to then dispense the pharmaceutical product. (See id. at 11:1323.)

E. Level of Ordinary Skill in the Art

A persona of ordinary skill in the art (POSA) in pharmaceutical prescriptions

as of October 23, 2000the earliest possible priority date for the 720 Patent

would typically have either a Pharm. D. or a BS in pharmacy with approximately 5-

10 years of experience and a license to practice as a registered pharmacist in any one

or more of the United States. (Ex. 1027 16.) An ordinarily skilled artisan may

work as part of a multi-disciplinary team and draw upon not only his or her own

skills, but also take advantage of certain specialized skills of others on the team, to

solve a given problem and care for varying patient populations. (Ex. 1027 17.)

VI. DETAILED EXPLANATION OF THE CHALLENGE

A. Ground 1: Claims 132 of U.S. Patent No. 6,315,720 are obvious under 35 U.S.C. 103(a) over Mitchell in view of Dishman and in further view of Cunningham and the knowledge of one of ordinary skill in the art.

1. Claim 1 is obvious over Mitchell in view of Dishman and in further view of Cunningham.

Claim 1 of the 720 Patent is written in Jepson format, meaning that the claim

first describes the scope of the prior art and then claims an improvement over the

17


prior art. Dow Chem. Co. v. Sumitomo Chem. Co., 257 F.3d 1364, 1368 (Fed. Cir. 2001).

Specifically, the Claim 1 preamble recites:

In a method for delivering a drug to a patient in need of the drug, while

avoiding the occurrence of an adverse side effect known or suspected of

being caused by said drug, wherein said method is of the type in which

prescriptions for said drug are filled only after a computer readable

storage medium has been consulted to assure that the prescriber is

registered in said medium and qualified to prescribe said drug, that the

pharmacy is registered in said medium and qualified to fill the

prescription for said drug, and the patient is registered in said medium

and approved to receive said drug, the improvement comprising:

(Ex. 1001 at 18:1727 (emphasis added).) Because a preamble is impliedly admitted

to be prior art when a Jepson claim is used, the patentee has admitted that the Claim

1 preamble is prior art, rather than a point of novelty. Pentec, Inc. v. Graphic Controls

Corp., 776 F.2d 309, 315 (Fed. Cir. 1985); see In re Glatt Air Techniques, Inc., 630 F.3d

1026, 1028 (Fed. Cir. 2011) (rejecting a claim as obvious in view of the admitted

prior art from the claim preamble and a single cited reference).

An ordinarily skilled artisan, when seeking to treat patients with a drug known

or suspected of causing an adverse side effect as in Claim 1s preamble, would look to

Mitchell for guidance on an approach that seeks to keep the drug available while

minimizing the hazard, and would garner from its recommendations for

delivering a drug to a patient in need of the drug, while avoiding the occurrence of an

adverse side effect known or suspected of being caused by said drug, as the

18


preamble requires. (Ex. 1010 at 105; Ex. 1027 76.) See In re Icon Health & Fitness, Inc.,

496 F.3d 1374, 1380 (Fed. Cir. 2007) (One skilled in the art would naturally look to

prior art addressing the same problem as the invention at hand, and in this case would

find an appropriate solution.).

With respect to Claim 1 of the 720 Patent, an ordinarily skilled artisan would

understand from Mitchell the desirability, when treating patients with drugs associated

with adverse side effects to certain risk groups, of defining a plurality of patient risk

groups based upon a predefined set of risk parameters for said drug as required by

Claim 1(a), defining a set of information to be obtained from said patient, which

information is probative of the risk that said adverse side effect is likely to occur if

said drug is taken by said patient as required by Claim 1(b), in response to said

information set, assigning said patient to at least one of said risk groups as required

by the first portion of Claim 1(c), and based upon said information and said risk

group assignment, determining whether the risk that said adverse side effect is likely

to occur is acceptable as required by Claim 1(d). (See Ex. 1010 at 10102, 105; Ex.

1027 78.)

Specifically, Mitchell teaches a patient-qualification checklist for assigning

patients to the risk groups to which a drug with teratogenic side effects, such as

isotretinoin, can and cannot be administered, as in Claim 1(a), based on the

unacceptable risk of teratogenic side effects to a fetus, as in Claim 1(d). (Ex. 1010 at

101; Ex. 1027 79, 94.) Mitchells risk group list includes, for example, women of 19


childbearing age and women who were at high risk of becoming pregnant, with

patients outside of these groups falling into a separate, lower risk category. (Ex. 1010

at 102, 105.) One of ordinary skill in the art would understand that a prescriber would

assign a patient to these various risk groups, as in the first portion of Claim 1(c), by

obtaining information from the patient such as their gender, and whether they are of

childbearing age or at a high risk of becoming pregnant, which are probative of

the risk that said adverse side effect is likely to occur if said drug is taken by said

patient, as in Claim 1(b). (Ex. 1010 at 102, 105; Ex. 1027 81.)

With respect to the second portion of Claim 1(c)entering said risk group in

said mediuman ordinarily skilled artisan would understand from Mitchell that

written records should be kept relating to risk group and related information.

(Ex. 1027 84.) For example, Mitchell recorded certain information via survey-

enrollment consent forms. (Ex. 1010 at 102.) Although Mitchell does not explicitly

mention keeping these records in a computer readable storage medium, because

Mitchell published the aggregated patient risk group information collected, it would

have been obvious to one of ordinary skill in the art that Mitchell inherently entered

the risk group information in a computer readable storage medium. (Ex. 1027 86.)

See Par Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 11941195 (Fed. Cir. 2014)

(We have recognized that inherency may supply a missing claim limitation in an

obviousness analysis.). Additionally, it would have been obvious to an ordinarily

skilled artisan that electronic records of information such as the patient risk group 20


assignment would be useful and easy to achieve through the entry into a computer.

(Ex. 1027 85.) See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007)

(finding obviousness where the skilled artisan would have had that reasonable

expectation of success that [application of the prior art technique] would work for its

intended purpose.).

Like Mitchell, which teaches guidelines for tightly-controlling the dispensing of

isotretinoin, Dishman discloses a program for tightly controlling the dispensing of the

antipsychotic drug clozapine. (See Ex. 1007 at 899901.) Armed with the disclosure of

Mitchell, an ordinarily skilled artisan would have been motivated to look to the system

disclosed in Dishman to further implement a computerized registry for delivering a

drug to a patient in need of the drug, while avoiding the occurrence of an adverse side

effect known or suspected of being caused by said drug. (Ex. 1001 at 18:1618; Ex.

1027 88.) See Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery, Inc., 774 F.3d 968, 977

(Fed. Cir. 2014) (When a claimed invention involves a combination of elements,

however, any need or problem known in the relevant field of endeavor at the time of

invention can provide a reason to combine.). Indeed, those of ordinary skill in the art

did look to the same isotretinoin system described in Mitchell with respect to the 720

Patent. (Ex. 1001 at 2:1335; Ex. 1033 at 1036.) See Rogers v. Desa Intl, Inc., 198 Fed.

Appx. 918, 922 (Fed. Cir. 2006) (Evidence that those of ordinary skill in the art in

fact combined the prior art teachings as claimed is certainly evidence that they were

21


motivated to do so. Such evidence shows the knowledge of the skilled artisan at the

time of the invention, which can provide the basis for a motivation to combine.).

With respect to the second portion of Claim 1(c)entering said risk group in

said mediumDishman discloses the storage of the patients clinical and

demographic information on a computer readable storage medium. (Ex. 1007 at

899.) For example, Dishman teaches that the NCCC requires that each hospital have a

computerized clozapine prescription lockout system[that] ties the hospitals

laboratory database to the outpatient pharmacy dispensing software. (Ex. 1007 at

900.) An ordinarily skilled artisan would have understood from the Dishman

reference that this computerized system must include the patients risk group

assignment data in order to determine which prescriptions should be locked out.

(Ex. 1027 91.) See Par Pharm., Inc., 773 F.3d at 11941195.

The final portion of the 720 Patents Claim 1Claim 1(e)requires that,

upon a determination that said risk is acceptable, generating a prescription approval

code to be retrieved by said pharmacy before said prescription is filled. (Ex. 1001 at

18:4042.) This mechanism would have been obvious to an ordinarily skilled artisan

upon reading Dishman, which discloses approval of acceptable risk through a registry

[that] permits community and hospital pharmacies to dispense clozapine only upon

the pharmacists verification that the WBC count is within acceptable limits. [T]he

lockout system prevents the filling of any clozapine prescription if the computer

22


notices three consecutive drops in WBC count. (Ex. 1007 at 899900; Ex. 1027

9596.)

Additionally, as the 720 Patent correctly states, [s]uitable computer readable

storage media will be apparent to one of ordinary skill in the art, once armed with

the teachings of the present application.) (Ex. 1001 at 5:1116.) An approval code

system such as that required by Claim 1(e)already known to those of ordinary skill

in the art at the timewould be an obvious mechanism for one of ordinary skill in

the art to use in order to implement Dishmans lockout system. (Ex. 1027 97.) See

Bayer Schering Pharma AG v. Barr Labs., Inc., 575 F.3d 1341, 1347 (Fed. Cir. 2009)

(When there is a design need or market pressure to solve a problem and there are a

finite number of identified, predictable solutions, a person of ordinary skill has good

reason to pursue the known options within his or her technical grasp. If this leads to

the anticipated success, it is likely the product not of innovation but of ordinary skill

and common sense.) (quoting KSR Intl Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).

It would have been further obvious to one of ordinary skill in the art to utilize

the Claim 1(e) approval codes to implement Dishmans lockout system, in light of

Cunninghams disclosure of an approval code lockout system for a pharmacy:

If authenticity is not established, it follows that the participating

pharmacy cannot dispense corresponding pharmaceutical product.

However, if authenticity is established then the pharmac[ys] terminal

dials the central computing station and data and information from the

pharmac[ys] authorization media and personal identification is uploaded 23


to the database of the central computing station 12. Assuming full

validation, the central computing station issues a pharmacy approval code and the pharmacy records that approval code on the actual presented product trial media 18. Once validation is established

the pharmacy then dispenses pharmaceutical trial product (Ex. 1008 at 11:68, 1723 (emphasis added); Ex. 1027 98.) See KSR Int'l Co., 550

U.S. at 41617 (holding that where a straightforward combination of references

[s]imply arranges old elements with each performing the same function it had been

known to perform and yields no more than one would expect from such an

arrangement, the combination is obvious.) (internal quotations and citations

omitted).

In view of the guidelines for the avoidance of treating pregnant patients with

isotretinoin taught by Mitchell, it would have been obvious to an ordinarily skilled

artisan to implement the methods disclosed in Dishman and Cunningham to limit

dispensation of a drug associated with adverse effects to certain risk groups.

(Ex. 1027 99.) See Abbott Labs v. Andrx Pharms., Inc., 452 F.3d 1331, 1345 (Fed. Cir.

2006) (finding substantial question of invalidity because the combination of references

for the reduction of systemic side effects would not be surprising and would not be

unexpected.). Therefore, an ordinarily skilled artisan treating a patient with a

teratogenic or other risk-laden drug in accordance with the guidelines disclosed in

Mitchell would look to published methods for limiting dispensation of other drugs

such as the clozapine registry found in Dishman and the approval code system

24


taught by Cunninghamand would view Claim 1 of the 720 Patent obvious in view of

these three references. (Ex. 1027 100.) See Dystar Textilfarben GmbH v. C.H. Patrick

Co., 464 F.3d 1356, 1361 (Fed. Cir. 2006) (The motivation need not be found in the

references sought to be combined, but may be found in any number of sources,

including common knowledge, the prior art as a whole, or the nature of the problem

itself.).

2. Dependent Claims 26 are obvious over the prior art of Ground 1, and more specifically over Mitchell in view of Dishman and in further view of the knowledge of one of ordinary skill in the art.

Claims 26 depend from Claim 1, and merely add limitations already known in

the field and obvious to one of ordinary skill in the art. Claim 2 requires that in

response to said risk group assignment, said patient is counseled as to the risks of

taking said drug and advised as to risk avoidance measures, while Claim 3 requires

that the Claim 2 counseling comprises full disclosure of said risks, Claim 4 requires

that said prescription is filled only following [the Claim 3] full disclosure and

informed consent of said patient, Claim 5 requires that said risk group assignment

and [Claim 4] informed consent is verified by said prescriber at the time that said

patient is registered in said computer readable storage medium, and Claim 6 requires

that said risk group assignment and said informed consent is transmitted to [the

Claim 5] computer readable storage medium by facsimile and interpreted by optical

character recognition software. (Ex. 1001 at 18:4358 (emphasis added).)

25


Mitchell teaches that the disclosed program encourages communication

between physicians and patients regarding the drugs teratogenic risk and the need to

prevent pregnancy, and that physicians were further provided with guidelines:

instructing them, for example, to warn patients of risks, obtain negative

pregnancy tests, and delay therapy until the second or third day of the

next normal menstrual period. They also included a patient-qualification

checklist, an information brochure for patients, contraceptive

information, information about and the necessary forms for a

contraception referral program (in which the manufacturer would

reimburse patients for a visit to another physician for contraceptive

counseling, and a consent form.

(Ex. 1010 at 101 (emphasis added), 105.) Mitchell additionally discloses that:

the manufacturer replaced traditional medication bottles with a 10-

capsule blister pack that contained information directed specifically at

women: the package included warnings about the risks of becoming

pregnant while taking isotretinoin or during the month after treatment,

an avoid pregnancy icon behind each capsule, and line drawings of

malformations associated with isotretinoin.

(Ex. 1010 at 101.) This information meets the counseling and disclosure requirements

of Claims 2 and 3. (Ex. 1027 104.)

In addition to the consent form contained in the physician information

discussed above, Mitchell further teaches of the need for patient consent and that

the program also included survey-enrollment consent forms. (Ex. 1010 at 102, 105.)

26


These teachings meet the disclosure and informed consent treatment prerequisites of

Claim 4.

Additionally, because Mitchell teaches that [t]he enrollment forms were

screened on receipt to exclude enrollments that were apparently fraudulent, men, and

previously enrolled women, and then [t]he eligible women were assigned, at

random, to be followed by one of the two methods, it would have been obvious to

one of ordinary skill in the art that the prescribing doctor would have verified the

disclosed requirements for treatmentsuch as the patients informed consent and risk

group assignmentwhen screening the enrollment forms and registering the patient

in the database for following. (Ex. 1010 at 102; Ex. 1027 10708.) Dishman further

renders this Claim 5 verification obvious, teaching that:

the pharmacist screens potential candidates before they undergo

extensive evaluation. The screening involves reviewing the patients case

with the requesting practitioner, reviewing the patients file, and

interviewing the patient to ensure that the patient and family members

are committed to weekly blood tests and follow-up. This screening

ensures that the physician does not waste time evaluating patients who

are ineligible for clozapine therapy. After a patient has been

determined eligible for clozapine therapy, the pharmacist forwards all

pertinent information to the NCCC. After NCCC approval, the

pharmacist enrolls the patient into the hospitals clozapine tracking

system, and clozapine therapy is begun.

(Ex. 1007 at 900 (emphasis added); Ex. 1027 10910.)

27


The previous disclosure also renders obvious to one of ordinary skill in the art

that the informed consent, risk group assignment, and other portions of the patients

file in the Dishman system are transmitted to the NCCCs database described above

with respect to Claim 1(c), and as required by the first portion of Claim 6. (Ex. 1027

112.) Dishman further teaches that, [a]fter each weekly follow-up appointment, the

pharmacist faxes a tracking sheet containing an evaluation of the patient to the

NCCC. (Ex. 1007 at 901.) Because it was within the knowledge of one of ordinary

skill in the art to transfer paper data into a computer database by fax, which is then

interpreted by optical character recognition [OCR] software, it would have been

obvious to one of ordinary skill in the art that the Dishman system would have used

OCR software to load the tracking sheet information into the NCCC database

(Ex. 1027 114.) Consequently, [i]t also would have been obvious to an ordinarily

skilled artisan that paper risk group assignments and informed consents could

similarly be transferred to the database through fax and OCR, as the last portion of

Claim 6 requires. (Ex. 1027 114.) See Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d

1324, 1329 (Fed. Cir. 2009) (KSR expanded the sources of information for a properly

flexible obviousness inquiry to include the background knowledge, creativity, and

common sense of the person of ordinary skill.).

28



Claims 710 depend from Claim 1, and merely add limitations already known

in the field and obvious to one of ordinary skill in the art. Claim 7 requires that the

information to be obtained from said patient prior to treatment includes the

results of diagnostic testing, while Claims 8, 9, and 10 respectively require that the

diagnostic testing is probative of the onset of said adverse side effect, is probative

of the concentration of said drug in a tissue of said patient, and comprises genetic

testing. (Ex. 1001 at 18:5967.)

Both Mitchell and Dishman disclose extensive diagnostic testing, including testing

probative of the onset of said adverse side effect, prior to treatment. Thus, both

Mitchell and Dishman teach the limitations of Claims 7 and 8. Specifically, Mitchell

teaches warnings about the need to have a negative blood pregnancy test before

starting therapy since birth malformations [are] associated with isotretinoin.

(Ex. 1010 at 101, 103.) Additionally, Dishman discloses that [t]he NCCC guidelines

require extensive patient evaluation and documentation. A complete physical

examination, including laboratory testing and electrocardiographic analysis, is

required. (Ex. 1007 at 900.)

With respect to Claim 9, it would have been obvious to one of ordinary skill in

the art to include, within the extensive diagnostic testing taught by Mitchell and

Dishman, testing for the drug concentration in patient tissue. (Ex. 1027 12223.)

29


Specifically, for any patient that had previously been treated with the drug, it would

have been obvious to one of ordinary skill in the art to conduct diagnostic testing

probative of the concentration of the drug remaining in the patients body. (Ex. 1027

122.) However, because many drugs do not generally distribute uniformly in the

body, but instead are preferentially absorbed by certain body tissues, one of ordinary

skill in the art would have further recognized the importance of performing diagnostic

testing that would be probative of the concentration of such a non-uniformly

distributing drug in the drugs target tissues. (Ex. 1027 12223.) See Tyco Healthcare

Group LP, 774 F.3d 968, 977 (Claims would have been obvious if they are nothing

more than a combination of familiar elements that yield predictable results.).

With respect to Claim 10, it would have been further obvious to one of

ordinary skill in the art to include genetic testing in the extensive diagnostic testing

taught by Mitchell and Dishman. (Ex. 1027 125.) Specifically, it was common in the

art at the time of the 720 Patent to conduct genetic testing at the same time as the

pregnancy testing taught in Mitchell. (Ex. 1027 124.) Similarly, [b]ecause there is

frequently a genetic component in schizophreniathe ailment treated in Dishman

one of ordinary skill in the art would have expected that the extensive diagnostic

testing in Dishman would have included genetic testing. (Ex.1027 126.) More

generally, because genetic testing was a well-known diagnostic procedure at the time

of the 720 Patent, it would have been obvious to one of ordinary skill in the art to

include genetic testing in the diagnostic testing that preceded such last-resort 30


treatments as those disclosed in Mitchell and Dishman. (Ex. 1027 127.) See Unigene

Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1361 (Fed. Cir. 2011) (This court has

observed that teachings from prior art, suggestions beyond the literal teachings of

those art references, or even motivations from the store of common knowledge of

one of ordinary skill in the art field (TSM)flexibly viewed and appliedprovide

the sources of evidence that an ordinary skilled artisan might have found and

combined at the time of the invention.).

4. Dependent Claims 1114 and 2025 are obvious over the prior art of Ground 1, and more specifically over Mitchell in view of the knowledge of one of ordinary skill in the art.

Claims 1114, and 2125 depend from Claim 1, and merely add limitations

already known in the field and obvious to one of ordinary skill in the art. Claims 11,

12, and 13 respectively require that the drugs associated side effect is likely to arise

in said patient, is likely to arise in a foetus carried by said patient, and is likely to

arise in a recipient or a foetus carried by a recipient of the bodily fluid of said patient,

while Claim 14 requires that the claim 12 recipient is a sexual partner of said

patient. (Ex. 1001 at 19:19.) Claim 22 requires that the drug is thalidomide. (Ex.

1001 at 19:3435.) Claim 21 requires that the drugs associated side effect comprises

a teratogenic effect, while Claims 23 and 24 respectively require that the Claim 21

teratogenic effect is likely to arise in a foetus carried by said patient, and is likely to

arise in a foetus carried by a recipient of the bodily fluid of said patient and Claim 25

requires that the Claim 24 recipient of the bodily fluid of said patient is a sexual

31


partner of said patient. (Ex. 1001 at 19:3233, 3642.) Claim 20 requires providing

said patient with a contraceptive device or formulation. (Ex. 1001 at 19:3031.)

Although Mitchell does not explicitly disclose that isotretinoins side effects arise

in the patient taking the drug, Mitchell discloses that its study relates to the drug

Accutane. (Ex. 1010 at 101.) One of ordinary skill in the art would have known to

look to Accutanes publicly-available FDA-approved drug label (included as a package

insert with any prescription of the drug) to determine whether isotretinoins side

effects arise in the patient taking the drug. (Ex. 1027 132.) The Accutane label prior

to the 720 Patents October 2000 filing stated in bold: WARNINGS: Psychiatric

Disorders: Accutane may cause depression, psychosis and rarely, suicidal ideation,

suicide attempts and suicide. (Ex. 1029 at 11.) Thus, [f]rom Mitchells disclosure, it

would have been obvious to one of ordinary skill in the art that isotretinoin side

effects arise in the patient taking the drugin the case of psychiatric disordersand

also in a fetus carried by the patient taking the drugin the case of teratogenicity,

satisfying Claims 11, 12, 21, 22 and 23. (Ex. 1010 at 101; Ex. 1027 134.)

By the time the 720 Patent was filed, it was well known to those of ordinary

skill in the art that certain drugs, including thalidomidedisclosed in Mitchell as a

drug that could potentially utilize Mitchells isotretinoin regimecould be found in

semen, and thus could be transmitted to a sexual partner of a male undergoing

treatment with the drug. (Ex. 1010 at 105; Ex. 1027 135.) For example, by 1982,

Mann and Lutwak-Mann had discovered that: 32


Thalidomide and tetracycline are drugs known to be strongly absorbed

by spermatozoa. Experiments indicating that thalidomide administered

to male rabbits adversely affects the pregnancy of females mated to these

males, for the first time drew attention to the until then unrecognized

eventuality of drug-induced pregnancy-wastage occurring by the paternal

route. Subsequently, it was shown that when [14C]thalidomide is

administered to male rabbits, the presence of the radioactive label can be

demonstrated in the semen (collected within the artificial vagina) within

a short time after ingestion, and is still detectable there some 12 days

later.

(Ex. 1018 at 78 (emphasis added).) Additionally, in 1997, Vanchieri wrote that

[b]ecause of a recent study showing thalidomide in rabbit semen and uncertainty

about its presence in human semen, both women and men receiving the drug will be

required to use contraception. (Ex. 1019 at 1.) For this reason, it was obvious to one

of ordinary skill in the art that a teratogenic drug, such as thalidomide, was likely to

cause side effects either in a sexual partner of a male being treated with the drug as in

Claims 14, 24, and 25, or in the fetus of this sexual partner as in Claims 13 and 23.

(Ex. 1027 13738.) See Perfect Web Techs., Inc., 587 F.3d at 1328 (Common sense

has long been recognized to inform the analysis of obviousness if explained with

sufficient reasoning.).

The teratogenic risks associated with isotretinoin had been well known since

the 1980s, as Mitchell discusses at length. (Ex. 1010 at 101 (The concern about

human teratogenicity proved well founded reports of pregnancies in exposed

33


women continued to accumulate, and by 1989 approximately 78 malformed infants

had been reported.).) For this reason, those of ordinary skill in the art at the time of

the 720 Patent readily recognized the importance of contraception to patients taking

isotretinoin. (Ex. 1027 142.) This is why Mitchells Pregnancy-Prevention Program

in Women of Childbearing Age Receiving Isotretinoin taught an aggressive

program designed to reduce the risk of pregnancy among women taking the drug

that included warnings about the need to have a negative blood pregnancy test

before starting therapy; to wait until the next menstrual period before starting therapy;

and to use effective birth control one month before starting therapy, during therapy,

and one month after completing it. (Ex. 1010 at 101, 103.) Mitchell further taught

providing an information brochure for patients, contraceptive information,

information about and the necessary forms for a contraception referral program (in

which the manufacturer would reimburse patients for a visit to another physician for

contraceptive counseling). (Ex. 1010 at 101.) In light of Mitchells teachings, it would

have been obvious to one of ordinary skill in the art that when the patient

participates in the contraception referral program, that doctor will likely provide the

patient with a contraceptive device or formulation as in Claim 20, in order to

accomplish Mitchells objective of ensuring that women of childbearing age taking

isotretinoin use effective contraception. (Ex. 1010 at 102; 1027 145.) See Sciele

Pharma, Inc., 684 F.3d at 1259. See Sciele Pharma, Inc. v. Lupin Ltd., 684 F.3d 1253, 1259

(Fed. Cir. 2012) (finding substantial question of validity because, [i]f a person of 34


ordinary skill can implement a predictable variation, 103 likely bars its

patentability) (quoting KSR, 550 U.S. at 417).

5. Dependent Claim 15 is obvious over the prior art of Ground 1, and more specifically over Mitchell in view of Dishman and in further view of the knowledge of one of ordinary skill in the art.

Claims 15 depends from Claim 1, and merely add limitations already known in

the field and obvious to one of ordinary skill in the art. Claim 15 requires f. defining

for each said risk group a second set of information to be collected from said patient

on a period basis; g. obtaining said second set of information from said patient; and h.

entering said second set of information in said medium before said patient is

approved to receive said drug. (Ex. 1001 at 19:1018.)

Both Mitchell and Dishman explicitly disclose defining information to be

collected and obtaining that information from the patient on a periodic basis as in

Claim 15(f) and (g). For example, Mitchell discloses that:

Each week, 100 women were randomly assigned to the group

interviewed by telephone. They were contacted three times: at the start

of therapy (within one month after enrollment), when we inquired about

the patients understanding of the hazards of isotretinoin and

compliance with the program; in the middle of therapy (between two

and four months after the start of the isotretinoin), when we inquired

about continued understanding of the hazards of isotretinoin and

compliance with the program; and six months after the completion of

therapy, when we asked about the occurrence of pregnancy during or

after treatment.

35


(Ex. 1010 at 102.) In addition, Mitchell teaches that:

Women not randomly assigned to the telephone group were sent a brief

questionnaire six months after starting isotretinoin to determine the date

on which they had completed or were expected to complete therapy.

They were then mailed a questionnaire six months after that date, which

included the same questions as the third telephone interview.

(Ex. 1010 at 102.) Mitchell further teaches that, [t]o minimize memory loss and biased

recall, we collected information on the behavior of physicians and patients at the start

of therapy as well as during treatment. (Ex. 1010 at 102.) Additionally, Dishman

teaches that [t]he manufacturer, Sandoz, requires all prescribers and patients to be

registered with the Clozaril National Registry, which requires weekly monitoring of

each patients white blood cell (WBC) count and limits medication dispensing to a

one-week supply. (Ex. 1007 at 899.)

Dishman further discloses that [p]hysicians at the NCCC review each clozapine

candidates file before granting approval for use and review weekly tracking sheets

that report patient status. [T]he pharmacist ensures that the psychiatry resident

orders the necessary laboratory tests, performs the required clinical evaluation, and

documents the results in a weekly tracking sheet, which the pharmacist forwards to

the NCCC. (Ex. 1007 at 900 (emphasis added).) As previously discussed above with

respect to the second portion of Claim 1(c)Dishman discloses the storage of the

patients weekly WBC count (and other collected information contained in the weekly

tracking sheet) on a computer readable storage medium. (See Ex. 1007 at 899.)

36


Because Dishman also teaches that this weekly review occurs before granting approval

for use, and that its lockout system will allow clozapine prescriptions to be

processed only when WBC counts are within the defined limits, it would have been

obvious to one of ordinary skill in the art that the weekly WBC test results must be

entered in the medium before said patient is approved to receive said drug, as

required by Claim 15(h). (Ex. 1007 at 900; Ex. 1027 15354.) See Perfect Web Techs.,

Inc., 587 F.3d at 1328.


Claims 1617 depend from Claim 1, and merely add limitations already known

in the field and obvious to one of ordinary skill in the art. Claim 16 requires that the

Claim 15 second set of information collected on a periodic basis comprises a survey

regarding said patients behavior and compliance with said risk avoidance measures,

while Claim 17 requires that the Claim 16 survey is conducted telephonically using

an integrated voice response system. (Ex. 1001 at 19:1924.)

Mitchell explicitly discloses Claim 16s requirement of a survey regarding said

patients behavior and compliance with said risk avoidance measures. For example,

Mitchells authors designed and conducted a survey to assess the compliance of

physicians and patients with the program and to identify the rate of pregnancy during

treatment with isotretinoin and during the month after treatment. (Ex. 1010 at 101

02.) Early in 1992, the questionnaire was modified to allow more complete

37


information to be obtained regarding sexual activity and birth control. (Ex. 1010 at

103.) Mitchell further discloses that, [a]mong women enrolled in this survey,

understanding of the teratogenic risks of isotretinoin and of the need to avoid

pregnancy was virtually universal. Compliance with other aspects of the program was

less complete, although in no case did compliance for any measure decline during the

study period. (Ex. 1010 at 104.)

Further, because one method of conducting the surveys in Mitchell was by

telephone, using an integrated voice response systemwhich was well known to

those of ordinary skill in the art at the timeas required by Claim 17, would have

been obvious to one of ordinary skill in the art. (Ex. 1027 158-61; see, e.g., Ex. 1017

at 61112, 623.) See In re Venner, 262 F.2d 91, 95 (C.C.P.A. 1958) (Furthermore, it is

well settled that it is not invention to broadly provide a mechanical or automatic

means to replace manual activity which has accomplished the same result.).

7. Dependent Claims 1819 and 2627 are obvious over the prior art of Ground 1, and more specifically over Mitchell in view of Dishman and in further view of the knowledge of one of ordinary skill in the art.

Claims 1819 and 2627 depend from Claim 1, and merely add limitations

already known in the field and obvious to one of ordinary skill in the art. Claim 18

requires that, where the patient is a female of childbearing potential, the Claim 15

second set of information collected on a periodic basis comprises the results of a

pregnancy test, while Claim 19 requires that the periodic interval for the Claim 18

38


pregnancy test comprises about 28 days. (Ex. 1001 at 19:2529.) Claim 26 similarly

requires that, where the drug has a teratogenic effect, the information to be obtained

from said patient includes the results of a pregnancy test, while Claim 27 adds to

the requirements of Claim 26 that said prescription is filled for no more than about

28 days. (Ex. 1001 at 19:4320:2.)

Mitchell explicitly discloses that, in light of isotretinoins teratogenicity,

women were warn[ed] about the need to have a negative blood pregnancy test before

starting therapy and that 78 percent [of women] were told to wait for pregnancy-

test results before starting isotretinoin as Claim 26 requires. (Ex. 1010 at 101

03.)

Mitchell further teaches obtaining periodic pregnancy test results from women

of childbearing age after isotretinoin treatment has begun: To identify compliance

with the program and the occurrence of pregnancy, the survey covered the treatment

period and the subsequent six months, a period long enough to allow identification of

pregnancies occurring as late as the first month after discontinuation of treatment.

(Ex. 1010 at 102 (emphasis added).) Mitchell also discloses that six months after the

completion of therapy, [the authors] asked about the occurrence of pregnancy during

or after treatment, and learned that there were 402 pregnancies during therapy.

(Ex. 1010 at 10102.) Dishman similarly teaches that, contraindications to clozapine

therapy include pregnancy, and so it would have been obvious to one of ordinary

39


skill in the art to also require a mid-treatment pregnancy test for Dishmans clozapine

patients upon a missed period. (Ex. 1007 at 900; Ex. 1027 167.)

Although neither reference teaches requiring periodic pregnancy tests before

prescribing the next cycle of drugs, Dishman does teach requiring WBC tests every

week before prescribing the next week of drugs, as discussed above with respect to

Claim 15(h). (Ex. 1007 at 899 (The manufacturer, Sandoz, requires all prescribers

and patients to be registered with the Clozaril National Registry, which requires

weekly monitoring of each patients white blood cell (WBC) count and limits

medication dispensing to a one-week supply.).) In light of Mitchell s requirement for

excluding pregnancy by a negative blood pregnancy before starting therapy it would

have been obvious to one of ordinary skill in the art to apply Mitchells pregnancy test

requirement to Dishmans periodic testing before prescription requirement, satisfying

Claim 18. (Ex. 1010 at 103; Ex. 1027 169.) See KSR Intl Co., 550 U.S. at 417.

Although Dishmans system requires testing every 7 days, and correspondingly

only allows patients to fill 7-day supply prescriptions, it was well known to one of

ordinary skill in the art that women may only become pregnant once during every 28-

day menstrual cycle. In light of this fact, when implementing Dishmans periodic

testing requirement to pregnancy testing, it would have been obvious to one of

ordinary skill in the art that the proper testing period for pregnancy is about 28 days,

as Claim 19 requires. (Ex. 1027 170.) See Sciele Pharma, Inc., 684 F.3d at 1259.

Further, applying Dishmans one-to-one correspondence between testing intervals 40


and prescription supplies, it would consequently have been obvious to one of

ordinary skill in the art to fill prescriptions for no more than about 28 days, as in

Claim 27. (Ex. 1027 171.) See KSR Intl Co., 550 U.S. at 417 ([I]f a technique has

been used to improve one device, and an ordinarily skilled artisan would recognize

that it would improve similar devices in the same way, using the technique is obvious

unless its actual application is beyond his or her skill.).

8. The added limitations of independent Claim 28 and dependent Claims 2932 are obvious over Mitchell in view of Dishman and in further view of Cunningham and knowledge of one of ordinary skill in the art.

Claim 28, although an independent claim, merely repeats the language of Claim

1 with a single added limitation already known in the field and obvious to one of

ordinary skill in the art. Claims 2932 depend from Claim 28, and similarly add

limitations already known in the field and obvious to one of ordinary skill in the art.

Claim 28(a)(e) maps precisely to Claim 1(a)(e), and so is obvious for the

reasons explained above with respect to Claim 1(a)(e). In addition, Claim 28 requires

that said adverse side effect is likely to arise in patients who take said drug in

combination with at least one other drug. (Ex. 1001 at 20:331.) Claims 29 and 30

respectively require that the information to be obtained from said patient is also

probative of the likelihood that said patient may take said drug and said other drug in

combination, and includes the results of diagnostic testing, while Claims 31 and

32 respectively require that the Claim 30 diagnostic testing comprises testing for

41


evidence of the use of said other drug and comprises testing for evidence which is

indicative of the onset of said adverse event. (Ex. 1001 at 20:3242.)

It would have been obvious to one of ordinary skill in the art that the adverse

effects described in Mitchell and Dishmanteratogenicity and agranulocytosis

would have also been likely to arise in patients who take said drug in combination

with at least one other drug, as required by Claim 28. (Ex. 1010 at 101; Ex. 1007 at

899; Ex. 1027 175.) See Perfect Web Techs., Inc., 587 F.3d at 1328.

As previously discussed with respect to Claims 7 and 8, both Mitchell and

Dishman disclose extensive diagnostic testing, including testing indicative of the onset

of said adverse side effect, prior to treatment. Thus, both Mitchell and Dishman teach

the limitations of Claims 30 and 32. Specifically, Mitchell teaches the need to have a

negative blood pregnancy test before starting therapy because of the drugs

teratogenic risk. (Ex. 1010 at 103, 105.) Additionally, Dishman discloses that [t

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IPR2015-01103